DESCRIPTION: (Applicant's Abstract) Long-term potentiation (LTP) is a cellular memory process which is the focus of intense interest. Most attention has so far been devoted to the role of synaptic kinases in this process. In view of the burgeoning interest in the cellular role of phosphatases, the place of these enzymes in the mechanism of LTP is of great relevance. As has been shown in a recent publication from our group, postsynaptic phosphatases act as a gate for LTP, which is controlled by the cAMP pathway. The postsynaptic phosphatases are arranged in a cascade involving calcineurin, protein phosphatase 1 (PP1) and inhibitory protein 1 (I-1). I-1 is the point where the cascade is inhibited by cAMP. In the present application it is proposed to further define the phosphatase cascade involved in LTP, by applying specific inhibitors of calcineurin and PP1, as well as biochemically measuring the phosphorylation of I-1 after high frequency synaptic stimulation (HFS). It is also proposed to investigate the mechanism for the influence of stimulation pattern on the cAMP-dependence of LTP which may be mediated by postsynaptic accumulation of calmodulin. Finally, the role of phosphatases and cAMP in the maintenance phase of LTP will be studied. The proposed experiments are based on a detailed and testable model, and on solid preliminary data. The importance of LTP for understanding memory processes, the fundamental importance of placing postsynaptic phosphatases in the theoretical framework for LTP, and the ubiquity and importance of cAMP signaling in the brain, all lend significance to the proposed project.